Fluorinated networks for anti-fouling surfaces

ABSTRACT

According to one or more embodiments, a method of making an antifouling coating includes forming a polythioaminal polymer by reacting a fluorinated primary amine with an aldehyde to form an intermediate imine, and then reacting the intermediate imine with a dithiol. The method further includes depositing the polythioaminal on a substrate, and increasing a temperature of the polythioaminal deposited on the substrate to crosslink the polythioaminal and increase a contact angle of the substrate with crosslinked polythioaminal.

BACKGROUND

The present invention relates in general to fluorinated polymers. Morespecifically, the present invention relates to fluorinated networks foranti-fouling surfaces.

The accumulation of microorganisms on wetted surfaces, or biofouling, isa common challenge for materials in a broad range of applications, suchas medical devices, marine instruments, food processing, and evendomestic drains. Generally, bacteria initiate biofouling by forming ofbiofilms, which are highly ordered adherent colonies, frequently withina self-produced matrix of extracellular polymeric substance. Biofilmscan accumulate, for example, on surfaces of medical devices, includingimplantable medical devices, as well as surfaces in hospital or medicalsettings.

Biofilms potentially release harmful toxins, and microorganisms easilyspread once biofilms are formed, which can lead to malfunction ofimplantable devices. Once a biofilm is formed on an implantable medicaldevice, extreme measures, such as removal of the infected implanteddevice from the patient's body are often the only viable managementoptions. Although disinfection techniques and prophylactic antibiotictreatment are used to prevent colonization during procedures, suchpractice is not always effective in preventing perioperative bacterialcolonization.

Antibiotic treatments to eliminate colonization and infection associatedwith implantable substances and devices can be limited in their abilityto eradicate bacteria and fungi involved in biofilm formation processes.For example, the concentration of antibiotics deep inside the biofilmcan be too low to be effective, which is in part due to limiteddiffusion. Generally, antibiotics also may be unable to eliminate allpathogen cells, which are usually accomplished by the immune system thatmay not function optimally in the presence of implantable devices.Furthermore, microorganisms possess the ability to persist, i.e., tobecome metabolically inactive and thus relatively resistant toantibiotics. Antibiotic resistance thus makes treating device-associatedinfections even more challenging. In fact, antibiotic resistance isfrequently encountered with microorganisms that cause device-associatedinfections (e.g., Enterococci and Staphylococci).

Consequently, considerable efforts were dedicated in recent years todeveloping antibacterial surfaces, in particular, in developingantifouling surfaces that prevent the adhesion of microorganisms.Current technologies, however, can suffer from poor long-termantibacterial performance and stability, the undesirable development ofbacterial resistance, or limited scalability to an industrial setting.

Accordingly, there is a need to prevent surfaces of medical devices fromforming biofilms and fouling. Forming polymeric coatings on surfaces ofmedical devices is one option to prevent biofouling.

Polythioaminals are a potential polymer that could be useful for formingsuch a coating. Polythioaminal polymers have potential applications innumerous arenas, for example, in facile preparation of therapeutic/drugconjugates, self-healing materials, and degradable hydrogels. Scheme 1below depicts a reaction for synthesizing polythioaminals usinghexahydrotriazine (HT). A dithiol (1) reacts with HT (2), releasing asubstituted primary amine (3) to form the substituted polythioaminal(4).

HTs, as shown in Scheme 1, and their thermosetting polymer analogues,PHTs, have attracted recent attention in the materials space becausethey exhibit a number of attractive properties, such as healability,recyclability, and even as detectors for heavy metals. HTs alsodemonstrate unique reactivity towards sulfur containing compounds.Hydrogen sulfide, for instance, readily reacts with HTs at roomtemperature to form dithioazine, where the six-member HT ring undergoesreplacement of two nitrogen atoms with sulfur. Organic thiols will alsoreact with HTs to produce thioaminals, as shown in Scheme 1, atransformation that has been exploited to generate linear step-growthpolythioaminals.

However, current synthetic routes, for example as shown in Scheme 1, forforming polythioaminals have some challenges that have made themsub-optimal for such applications. A limiting factor in thepolymerization shown in Scheme 1 above is the identity of thesubstituent of the HT (2) (“X”). In particular, as the size of “X”increases, the molecular weight of the polymer decreases. Therefore,high molecular weight polymers are only generated with short aliphaticHT substituents, which restrict the chemical diversity of the resultingpolymers.

The relationship between the size of the HT (2) substituents, “X,” andthe product polythioaminal (4) molecular weight is the result of thesubstituted primary amine (3) generated after the reaction of thedithiol (1) with the HT (2). The formation of this amine (3) influencesthe reaction equilibrium, preventing further reaction of thiols (1) withHTs (2) and necessitating subsequent removal (in vacuo) to access highmolecular weight polythioaminals (4). Therefore, as the mass of thesubstituent (“X”) increases, the volatility of the liberated substitutedprimary amine (3) is reduced, thereby making the polymerizationincreasingly difficult to drive to high molecular weights.

Therefore, alternative chemistries that can provide access topolythioaminals that are not restricted by the volatility of a sideproduct are needed. Such chemistries can provide access to morechemically diverse polymers, which can allow polythioaminal polymers tobe used as coatings on surfaces, such as medical devices.

SUMMARY

Embodiments of the present invention are directed to a method of makingan antifouling coating. The method includes forming a polythioaminalpolymer by reacting a fluorinated primary amine with an aldehyde to forman intermediate imine, and then reacting the intermediate imine with adithiol. The method further includes depositing the polythioaminal on asubstrate, and increasing a temperature of the polythioaminal depositedon the substrate to crosslink the polythioaminal and increase a contactangle of the substrate with crosslinked polythioaminal. Forming theintermediate imine and then reacting the intermediate imine with adithiol provides the advantage of being able to form a polythioaminalwithout the use of HT monomers that form amine side products, whichallows incorporation of larger molecular weight substituents for thefluorinated primary amine.

According to one or more embodiments, a method of making a hydrophobicantifouling coating includes forming a linear polythioaminal polymer byreacting a fluorinated dianiline derivative with a paraformaldehyde toform an intermediate imine, and then reacting the intermediate iminewith a dithiol. The method includes disposing the linear polythioaminalpolymer on a surface of a substrate, and increasing a temperature of thelinear polythioaminal polymer to crosslink the linear polythioaminalpolymer and increase a contact angle of the substrate with crosslinkedpolythioaminal. Forming the intermediate imine and then reacting theintermediate imine with a dithiol provides the advantage of being ableto form a polythioaminal without the use of HT monomers that form amineside products, which allows incorporation of larger molecular weightsubstituents for the fluorinated aniline.

According to one or more embodiments, a method of making a hydrophobiccoating on a surface of a medical device includes forming apolythioaminal polymer by reacting a fluorinated aniline with analdehyde to form an intermediate imine, and then reacting theintermediate imine with a dithiol. The method includes depositing thepolythioaminal polymer on a surface of the medical device. The methodfurther includes increasing a temperature of the polythioaminal polymerto increase a contact angle of the polythioaminal polymer with thesurface of the medical device. Forming the intermediate imine and thenreacting the intermediate imine with a dithiol provides the advantage ofbeing able to form a polythioaminal polymer without the use of HTmonomers that form amine side products, which allows incorporation oflarger molecular weight substituents for the fluorinated aniline.

Additional technical features and benefits are realized through thetechniques of the present invention. Embodiments and aspects of theinvention are described in detail herein and are considered a part ofthe claimed subject matter. For a better understanding, refer to thedetailed description and to the drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

The specifics of the exclusive rights described herein are particularlypointed out and distinctly claimed in the claims at the conclusion ofthe specification. The foregoing and other features and advantages ofthe embodiments of the invention are apparent from the followingdetailed description taken in conjunction with the accompanying drawingsin which:

FIG. 1 depicts a cross-sectional side view of a coating formed on asubstrate according to one or more embodiments of the invention;

FIG. 2A depicts a reaction scheme and nuclear magnetic resonance (NMR)spectrum according to one or more embodiments of the invention;

FIG. 2B depicts a graph showing % conversion of a starting material overtime according to one or more embodiments of the invention;

FIG. 3A depicts a reaction scheme and NMR spectrum according to one ormore embodiments of the invention;

FIG. 3B depicts a graph showing mole % of a starting material andconverted product formation over time according to one or moreembodiments of the invention;

FIG. 4A depicts a reaction scheme according to one or more embodimentsof the invention;

FIG. 4B depicts a gel permeation chromatography (GPC) spectrum showingformation of a product according to one or more embodiments of theinvention; and

FIG. 5 depicts a method for forming a coating on a substrate accordingto one or more embodiments of the invention.

The diagrams depicted herein are illustrative. There can be manyvariations to the diagram or the operations described therein withoutdeparting from the spirit of the invention. For instance, the actionscan be performed in a differing order or actions can be added, deletedor modified. Also, the term “coupled” and variations thereof describeshaving a communications path between two elements and does not imply adirect connection between the elements with no interveningelements/connections between them. All of these variations areconsidered a part of the specification.

In the accompanying figures and following detailed description of thedisclosed embodiments, the various elements illustrated in the figuresare provided with two or three digit reference numbers. With minorexceptions, the leftmost digit(s) of each reference number correspond tothe figure in which its element is first illustrated.

DETAILED DESCRIPTION

Turning now to an overview of technologies that are more specificallyrelevant to aspects of the invention, alternative chemistries to formpolythioaminals that are not restricted by the volatility of a sideproduct are needed. Such chemistries can provide access to morechemically diverse polymers, which can allow polythioaminal polymers tobe used as coatings on surfaces, such as medical devices.

Turning now to an overview of the aspects of the invention, one or moreembodiments of the invention address the above-described shortcomings byproviding methods of making networks and coatings with highlyfluorinated polythioaminals. The networks and coatings are disposed ontosurfaces that are susceptible to biofouling, for example, on surfaces ofmedical devices. The described reaction schemes are an alternativesynthetic strategy to form polythioaminals without the use of HTmonomers. Stable imine intermediates are formed that react with thiolswith a high conversion rate. The reactions described herein form highlyfluorinated networks and hydrophobic coatings on susceptible surfaces,for example, of medical devices, marine instruments, food processingsurface, or domestic drains, to provide an antifouling surface.

The above-described aspects of the invention address the shortcomings ofother described approaches by allowing the incorporation of largermolecular weight substituents for the nitrogen-containing monomericstarting material. Thus, high molecular weight polythioaminals can beformed. The high molecular weight polymers also include fluorine, whichcan then function as antifouling coatings to prevent biofilm formation.

Turning now to a detailed description of aspects of the presentinvention, FIG. 1 shows an antifouling coating 102 on the surface of asubstrate 101. The coating includes fluorinated polythioaminal polymers,which will be described in further detail below. The coating 102 is anantifouling coating that can be formed on the surface of a medicaldevice or a surface in a medical setting (such as a hospital) that issusceptible to contamination. The one or more fluorines present in thepolythioaminal coatings provide the antifouling properties.

Non-limiting examples of implantable medical devices include, forexample, prosthetic joints, heart valves, artificial hearts, vascularstents and grafts, cardiac pacemakers, defibrillators, nerve stimulationdevices, gastric pacers, vascular catheters and ports (e.g.,Port-A-Cath). The surfaces of these implanted materials and devicesrepresent areas in which bacterial colonization and subsequent biofilmformation is difficult to diagnose and treat.

As described in further detail below, primary amines substituted withone or more electron withdrawing fluorine groups form reactiveintermediate imines in the presence of an aldehyde. The reactive imineintermediate is quickly consumed in a self-trimerization reaction, inthe absence of additional reactants. But, when the intermediate imine isreacted with a thiol, the self-trimerization reaction is suppressed. Thethiol condenses with the imine intermediate to generate apolythioaminal. Thus, the reactions for forming the polythioaminal areefficient. The intermediate imine is quickly consumed by any thiolpresent, preventing competitive side reactions, for example anyself-trimerization reactions.

Scheme 2 below is a reaction for forming a thioaminal according to oneor more embodiments of the present invention. A substituted primaryamine (1) that includes one or more electron withdrawing fluorinesreacts with an aldehyde (2) to form a reactive intermediate (3).According to one or more embodiments, the reactive intermediate is areactive intermediate imine. The reactive intermediate (3) reacts with athiol (4) to drive the reaction that forms a thioaminal (5). The one ormore electron withdrawing fluorine groups stabilize in situ imineformation.

Scheme 3 is a reaction for initially forming the reactive intermediateaccording to one or more embodiments of the present invention. Asmentioned above, reactive intermediate (8) is quickly consumed in aself-trimerization reaction to form substituted hexahydrotriazine (HT)(9) in the absence of additional reactants, such as the thiol in Scheme2. According to one or more embodiments, the reactive intermediate is areactive intermediate imine. The substituted HT (9) includes thefluorines present on the starting fluorinated amine (6). The reactiveintermediate (8) is useful in the context of a polymer-forming reactionbecause its formation is quantitative and quickly consumed by any thiolpresent to prevent any competitive reaction in the formation ofsubstituted HT (9).

The fluorinated amine (6) includes a fluorinated aromatic ring structureand a primary amine according to one or more embodiments, for example,fluorinated aniline. In one exemplary embodiment, the fluorinatedaniline is 4-trifluoromethyl aniline. The fluorinated amine includes oneor more electron withdrawing fluorine groups, for example, one or moretrifluoromethyl groups on an aromatic ring structure. The one or moretrifluoromethyl groups can be present at any location on the aromaticring.

The fluorinated amine (6) can include one or more additionalsubstitutions on the aromatic ring. According to one or moreembodiments, the fluorinated amine (6) includes one or more aromaticrings, which each include one or more fluorine substitutions and one ormore amine substitutions.

According to exemplary embodiments, the fluorinated amine (6) has thefollowing structure:

According to one or more exemplary embodiments, the fluorinated amine(6) has the following structure:

The aldehyde (7) is formaldehyde (methanal) or paraformaldehydeaccording to one or more embodiments. Other non-limiting examples ofaldehydes that can be used include ethanal, propanal, butanal, or acombination thereof. The aldehyde is any aldehyde that can react withthe fluorinated amine (6) to form an intermediate imine (8).

The reactive intermediate (8) formed depends on the identities of thefluorinated amine (6) and the aldehyde (7). Imine formation from afluorinated primary amine and aldehyde occurs as follows:R₁—NH₂+R₂CHO→R₁—N=C—R₂+H₂O. Water is eliminated in the reaction. R₁includes one or more fluorine atoms or groups, such as trifluoromethylgroups. R₂ is H.

The substituted HT (9) results as the reactive intermediate (8)self-trimerizes. As mentioned above, this reaction is displaced in thepresence of thiols.

Scheme 4 is a reaction for converting the reactive intermediate (8) intoa thioaminal (11) according to one or more embodiments of the invention.According to one or more embodiments, the reactive intermediate is areactive intermediate imine. When the reactive intermediate (8) isintroduced to a thiol (10), a thioaminal (11) is formed, and theformation of the HT (9) in Scheme 3 is suppressed. The thioaminal (11)is formed in high yield and independent of the identities of thesubstitutions on the fluorinated amine (6) starting material.

The fluorinated amine (6) is a fluorinated primary amine, and thealdehyde is paraformaldehyde according to one or more embodiments. Theformation of the thioaminal (11) occurs as follows:R₁—NH₂+R₂CHO→[R₁—N=CHR₂]+HS—R₃→R₁—NH—CHR₂—SR₃. R₁ includes one or morefluorine atoms or groups, such as trifluoromethyl groups. R₂ is H or ahydrocarbon chain with any number of carbons. In some embodiments, R₂includes from 1 to 10 carbons. R₃ is a hydrocarbon chain with any numberof carbons. In some embodiments, R₃ includes from 1 to 20 carbons.

A polymeric thioaminal (polthioaminal) is also formed by apolycondensation reaction. An imine is formed as an intermediate. Scheme5 shows a fluorine substituted aniline (12) reacting with aldehyde (7)to form reactive intermediate (13). The reactive intermediate (13)reacts with dithiol (14) to form the polythioaminal (15).

The substituted aniline (12) includes at least one aromatic ring and atleast one primary amine. The substitutions on the aniline (12) includeone or more fluorine atoms or fluorine-containing groups, for example,trifluoromethyl groups. The substituted aniline (12) is a diamineaccording to one or more embodiments. The substituted aniline (12) is afluorinated dianiline according to one or more embodiments. According toan exemplary embodiment, the substituted aniline (12) is(hexafluoroisopropylidene)dianiline.

The aldehyde (7) includes one or more carbons. According to one or moreembodiments, the aldehyde (7) is formaldehyde or paraformaldehyde.

The reactive intermediate (13) is an intermediate that reacts with thedithiol (14) to form the polythioaminal (15). According to an exemplaryembodiment, the dithiol (14) is 1,6-hexanedithiol. According to otherembodiments, the dithiol (14) is poly(ethylene) glycol dithiol ordithioerythritol. In other embodiments, the dithiol (14) includes ahydrocarbon chain with any length carbon chain, any polyalcohol, or anylength polyethylene glycol dithiol.

The polymeric polythioaminal (15) proceeds to high conversion, byin-situ forming a reactive intermediate imine (13) that condenses withthe dithiol (14) to generate the polythioaminal (15).

The reaction occurs as follows:NH₂—R₁—NH₂+R₂CHO→[R₂—CH=N—R₁—N=CH—R₂]+HS—R₃—SH→—[S—R₃—S—CH(R₂)—NH—R₁—NH—CH(R₂)]_(n)-S—R₃—SH.R₁ includes one or more aromatic rings and one or more fluorinecontaining groups. R₂ and R₃ include hydrocarbon chains, with the numberof carbons not being limited. The polythioaminal (15) has an “n” ofabout 1 to about 15.

The reaction proceeds to produce a polythioaminal (15) of high molecularweight. According to one or more embodiments, the polythioaminal has amolecular weight of less than 8,000 g mol¹. In some other embodiments,the polythioaminal has a molecular weight in a range from about 5,000 toabout 25,000 g mol⁻¹.

In contrast to Scheme 1, for example, amines affecting the reactionequilibrium are not being liberated. The liberated amine in Scheme 1must be removed to drive the reaction towards formation of thethioaminal. Further, as mentioned with reference to Scheme 1, theidentities of the substituents on the amine affect the amine'svolatility, with larger substituents decreasing the volatility, andtherefore, reducing the conversion rate to the high molecular weightpolythioaminals.

Non-limiting examples of substituents can be present on the substitutedprimary amine (1) in Scheme 2, fluorinated amine (6) in Schemes 3 and 4,and substituted aniline (12) in Scheme 5 include fluorine groups, aminegroups, CF₃ groups, or a combination thereof.

High molecular weight substituents can be present on the fluorinatedamine starting materials. According to one or more embodiments, thesubstituted primary amine (1) in Scheme 2, fluorinated amine (6) inSchemes 3 and 4, and substituted aniline (12) in Scheme 5 can havemolecular weights of at least 31 g mol⁻¹, or in a range from about 100to about 20,000 g mol⁻¹.

Because the reactions described herein do not liberate an amine, theconversion to the polythioaminal occurs at a high rate, regardless ofthe substitutions on the starting material. According to one or moreembodiments, at least 99.99% of the initial fluorinated primary amine isconverted to the polythioaminal. According to one or more embodiments,about 100% of the initial fluorinated primary amine is converted to thepolythioaminal.

The temperature at which the reactions proceed to form thepolythioaminals affects the extent of crosslinking that occurs to form anetwork that can be used as a hydrophobic antifouling coating on asubstrate. At lower temperatures, for example, from about 25 to about100° C., linear polymers are formed. As the temperature is increased toabout 110 to about 200° C., the linear polymers undergo multiplesubstitutions at the nitrogen to form a cross-linked network. Accordingto one or more embodiments, the temperature is increased to at least100° C. to crosslink the linear polythioaminal and form a network on asurface of a substrate.

Thus, as shown in FIG. 5, a linear polyaminal 502 can be disposed ontothe surface of a substrate 501. The polydispersity index (PDI) of thelinear polythioaminal 502 is about 2 according to one or moreembodiments. The substrate 502 and linear polythioaminal 502 is heatedto form a coating 503 (or film) of a crosslinked network 504 of thepolyaminal. According to one or more embodiments, the coating 503 is afilm that takes the shape of the substrate 501. As the fluorine contentof the starting material increases, the contact angle of the resultingcoating 503 increases. The contact angle increases to at least 100°according to some embodiments. The PDI of the crosslinked network 504also increases as the temperature is increased.

According to one or more embodiments, a linear polyaminal formed asdescribed herein is disposed, for example by spin-coating, onto thesurface of a substrate. The substrate is then heated to form across-linked network on the surface of the substrate.

According to one or more embodiments, a method of making an antifoulingcoating includes forming a polythioaminal polymer by reacting afluorinated primary amine with an aldehyde to form an intermediateimine, and then reacting the intermediate imine with a dithiol. Themethod further includes disposing the polythioaminal on a substrate. Themethod further includes increasing a temperature of the polythioaminaldisposed on the substrate to crosslink the polythioaminal and increase acontact angle of the substrate with crosslinked polythioaminal.

Forming the intermediate imine and then reacting the intermediate iminewith a dithiol provides the advantage of being able to form apolythioaminal without the use of HT monomers that form amine sideproducts, which allows incorporation of larger molecular weightsubstituents for the fluorinated primary amine.

Embodiments where the fluorinated primary amine is a diamine haveadvantages of polymerizing the polythioaminal to even higher molecularweight.

According to one or more embodiments, a method of making a hydrophobicantifouling coating includes forming a linear polythioaminal polymer byreacting a fluorinated dianiline derivative with a paraformaldehyde toform an intermediate imine, and then reacting the intermediate iminewith a dithiol. The method includes disposing the linear polythioaminalpolymer on a surface of a substrate. The method further includesincreasing a temperature of the linear polythioaminal polymer tocrosslink the linear polythioaminal polymer and increase a contact angleof the substrate with crosslinked polythioaminal.

Forming the intermediate imine and then reacting the intermediate iminewith a dithiol provides the advantage of being able to form apolythioaminal without the use of HT monomers that form amine sideproducts, which allows incorporation of larger molecular weightsubstituents for the fluorinated primary amine.

Embodiments where the contact angle is at least 100° have advantages offorming a thick hydrophobic coating that prevents biofilm.

According to one or more embodiments, a method of making a hydrophobiccoating on a surface of a medical device includes forming apolythioaminal polymer by reacting a fluorinated aniline with analdehyde to form an intermediate imine, and then reacting theintermediate imine with a dithiol. The method includes disposing thepolythioaminal polymer on a surface of the medical device. The methodfurther includes increasing a temperature of the polythioaminal polymerto increase a contact angle of the polythioaminal polymer with thesurface of the medical device.

Embodiments where increasing the temperature of the polythioaminalpolymer induces crosslinking by forming substitutions at nitrogen groupshave advantages of forming a highly crosslinked network that is formedafter a linear polymer is deposited on the surface of the medicaldevice.

EXAMPLES Example 1

To explore the potential of imines to form thioaminals, model reactionswere performed with aniline derivatives substituted withelectron-withdrawing trifluoromethyl substituents. FIG. 2A depicts thereaction scheme and corresponding nuclear magnetic resonance (NMR)spectra for the reaction of 4-trifuoromethyl aniline (1) withparaformaldehyde (1.5 eq.) in acetonitrile at 70° C. 4-trifluoromethylaniline (1) formed an intermediate imine (2) that quickly underwentcyclization to form trimer (3), as shown by NMR monitoring.

The reaction was monitored over the course of 20 hours, with spectrataken after every 40 minutes. From ¹H-NMR peaks shown in FIG. 2A, thepeaks (a) associated with the starting material (1) decreased inintensity as several new peaks (b) and (d), associated with the imine(2), begin to grow. However, after a period of about 500 minutes (8.3hours), the new peaks decreased in intensity as peak (c), associatedwith trimer (3) began to grow. During the course of the reaction, peaksassociated with the decomposition of paraformaldehyde grew in intensity.

Using shorter reaction times, peaks associated with imine (2) wereconfirmed using a combination of ¹³C-NMR and 2D-NMR (not shown). ¹³C-NMRwas useful in providing diagnostic indications of the formation of bothimine (2) and trimer (3) where downfield resonances could be observedcharacteristic of the carbon associated with protons in peak (d). Theseresults showed that the formation of imine (2) was a reactiveintermediate that was quickly consumed in the self-trimerization to formtrimer (3) in about 70% conversion, as shown in FIG. 2B. The generationof imine (2) was thus useful as a polymer forming reaction because itsgeneration was quantitative.

Example 2

The efficiency for the in-situ generation of imines and subsequentreaction with the presence of thiols to form thioaminals was alsoexplored using a model NMR scale reaction using 4-trifuoromethyl aniline(1) in the presence of 1-butane thiol (4) (1 eq.) and paraformaldehyde(1.5 eq.) at 70° C. in CD₃CN. FIG. 3A depicts the reaction scheme andcorresponding NMR spectra for the reaction of 4-trifuoromethyl aniline(1) with paraformaldehyde (1.5 eq.) in acetonitrile at 70° C. and1-butane thiol (4).

Interestingly, in the presence of a thiol, the formation of trimer (3)was completely suppressed. No diagnostic peaks were observedcorresponding with the trimer (3) when observing either ¹H or ¹³Cnuclei. Conversion to the thioaminal could be followed by the growth ofpeaks (b) and (c), associated with polythioaminal (4), while thosecorresponding with 4-trifluoroaniline (1) decreased in intensity. Afterabout 20 hours, the generation of thioaminal (4) plateaued at nearlyquantitative conversion (about 90%), as shown in FIG. 3B.

Example 3

To exploit the imine-thiol reaction in a polycondensation reaction,4,4′-(hexafluoroisopropylidene)dianiline was reacted in bulk with1,6-hexanedithiol in equimolar ratios with an excess of paraformaldehyde(2.5 eq.) at 85° C., as shown in FIG. 4A. Over the course of 18 hours,the reaction proceeded to high conversion. A polymeric material wasgenerated from the in-situ generation of a reactive intermediate iminethat condensed with 1,6-hexanedithiol to generate a polythioaminal (seeFIG. 4A). The product polythioaminal was confirmed by gel permeationchromatography (GPC), as shown in FIG. 4B. The M_(W) of thepolythioaminal was 19,238 g mol⁻¹ (M_(n)=10,689 g mol⁻¹).

Example 4

To highlight the effect of the electron withdrawing fluorines on thegeneration of the polymer, a control reaction was performed using amonomer without trifluoromethyl substituents,4,4′-diaminodiphenylmethane, using the same reaction conditionsdescribed in Example 3 and the same dithiol. Only a low molecular weightpolymer was generated (M_(W)=4,810 g mol−1, M_(n)=2,658 g mol−1).Without being bound by theory, the lower molecular weight was believedto result from an uncontrolled series of reactions that included theformation of cyclic products, imine, and reaction with either of thesewith the dithiol. Because amines severely reduce the formation ofthioaminals, any amines generated, liberated, or those remainingunreacted can prevent the polycondensation reaction from reaching ahigher molecular weight.

Example 5

The role of temperature on the formation of polythioaminals wasassessed. It was found that at lower temperatures, only linearpolythioaminals are formed, in which the polydispersity index (PDI) is˜2.00. However, as the temperature increased to 110° C., the linearpolymer began to undergo multiple substitutions at the nitrogen, whichincreased the PDI and formed a network (see FIG. 5 for example).

Example 6

A polythioaminal was prepared. A fluorinated amine (A) having thefollowing structure was combined with paraformaldehyde as follows.

770 mg of A (2.35 mmol)+140.8 mg paraformaldehyde+358 μL hexane dithiolin 2 mL of N-methyl pyrrolidone were added to a scintillation vial witha Teflon coated stir-bar. The vial was purged with nitrogen and thensealed and heated to 70° C. in an inert nitrogen atmosphere. Thereaction was run over the course of about 60 hours to build up themolecular weight of the linear polymer. Oligomers were observed by gelpermeation chromatography (GPC). The linear oligomer could be coated ona silicon wafer by drop-cast method then was cured in a vacuum ovenovernight at 140° C.

Example 7

A polythioaminal was prepared. A fluorinated amine (B) having thefollowing structure was combined with paraformaldehyde as follows.

0.765 g (2.29 mmol) B+137.3 mg paraformaldehyde+350 μL hexane dithiolwere added to a scintillation vial followed by 1.5 mLN-methylpyrrolidone. The vial flushed with nitrogen. The vial was thensealed and heated to 75° C. After about 24 hours, the molecular weightwas observed by GPC, which was about 4,200 g mol⁻¹. After about 94 hoursof heating, the molecular weight increased slightly to 6,600 g mol⁻¹,and after about 110 hours, the molecular weight again increased to 6,800g mol⁻¹. The PDI also increased and after 24 hours reached 2.03. After94 hours, the PDI increased to 2.5, and after 110 hours, the PDI was2.6. When the temperature was increased to 110° C., the solution beganto gel, which indicated a network polymer was forming. The solublefraction of polymer exhibited a molecular weight of 100,500 g mol¹ witha broad PDI of 16.4.

Various embodiments of the present invention are described herein withreference to the related drawings. Alternative embodiments can bedevised without departing from the scope of this invention. Althoughvarious connections and positional relationships (e.g., over, below,adjacent, etc.) are set forth between elements in the followingdescription and in the drawings, persons skilled in the art willrecognize that many of the positional relationships described herein areorientation-independent when the described functionality is maintainedeven though the orientation is changed. These connections and/orpositional relationships, unless specified otherwise, can be direct orindirect, and the present invention is not intended to be limiting inthis respect. Accordingly, a coupling of entities can refer to either adirect or an indirect coupling, and a positional relationship betweenentities can be a direct or indirect positional relationship. As anexample of an indirect positional relationship, references in thepresent description to forming layer “A” over layer “B” includesituations in which one or more intermediate layers (e.g., layer “C”) isbetween layer “A” and layer “B” as long as the relevant characteristicsand functionalities of layer “A” and layer “B” are not substantiallychanged by the intermediate layer(s).

The following definitions and abbreviations are to be used for theinterpretation of the claims and the specification. As used herein, theterms “comprises,” “comprising,” “includes,” “including,” “has,”“having,” “contains” or “containing,” or any other variation thereof,are intended to cover a non-exclusive inclusion. For example, acomposition, a mixture, process, method, article, or apparatus thatcomprises a list of elements is not necessarily limited to only thoseelements but can include other elements not expressly listed or inherentto such composition, mixture, process, method, article, or apparatus.

Additionally, the term “exemplary” is used herein to mean “serving as anexample, instance or illustration.” Any embodiment or design describedherein as “exemplary” is not necessarily to be construed as preferred oradvantageous over other embodiments or designs. The terms “at least one”and “one or more” are understood to include any integer number greaterthan or equal to one, i.e. one, two, three, four, etc. The terms “aplurality” are understood to include any integer number greater than orequal to two, i.e. two, three, four, five, etc. The term “connection”can include an indirect “connection” and a direct “connection.”

References in the specification to “one embodiment,” “an embodiment,”“an example embodiment,” etc., indicate that the embodiment describedcan include a particular feature, structure, or characteristic, butevery embodiment may or may not include the particular feature,structure, or characteristic. Moreover, such phrases are not necessarilyreferring to the same embodiment. Further, when a particular feature,structure, or characteristic is described in connection with anembodiment, it is submitted that it is within the knowledge of oneskilled in the art to affect such feature, structure, or characteristicin connection with other embodiments whether or not explicitlydescribed.

For purposes of the description hereinafter, the terms “upper,” “lower,”“right,” “left,” “vertical,” “horizontal,” “top,” “bottom,” andderivatives thereof shall relate to the described structures andmethods, as oriented in the drawing figures. The terms “overlying,”“atop,” “on top,” “positioned on” or “positioned atop” mean that a firstelement, such as a first structure, is present on a second element, suchas a second structure, wherein intervening elements such as an interfacestructure can be present between the first element and the secondelement.

The terms “about,” “substantially,” “approximately,” and variationsthereof, are intended to include the degree of error associated withmeasurement of the particular quantity based upon the equipmentavailable at the time of filing the application. For example, “about”can include a range of ±8% or 5%, or 2% of a given value.

The descriptions of the various embodiments of the present inventionhave been presented for purposes of illustration, but are not intendedto be exhaustive or limited to the embodiments disclosed. Manymodifications and variations will be apparent to those of ordinary skillin the art without departing from the scope and spirit of the describedembodiments. The terminology used herein was chosen to best explain theprinciples of the embodiments, the practical application or technicalimprovement over technologies found in the marketplace, or to enableothers of ordinary skill in the art to understand the embodimentsdescribed herein.

What is claimed is:
 1. A method of making an antifouling coating, themethod comprising: forming a polythioaminal polymer by reacting afluorinated primary amine with an aldehyde to form an intermediateimine, and then reacting the intermediate imine with a dithiol;depositing the polythioaminal on a substrate; and increasing atemperature of the polythioaminal deposited on the substrate tocrosslink the polythioaminal and increase a contact angle of thesubstrate with crosslinked polythioaminal.
 2. The method of claim 1,where the fluorinated primary amine is a diamine.
 3. The method of claim1, where the fluorinated primary amine comprises at least one aromaticring.
 4. The method of claim 1, where the fluorinated primary amine is adianiline.
 5. The method of claim 1, wherein depositing thepolythioaminal on the substrate is by spin-coating.
 6. The method ofclaim 1, where the aldehyde is paraformaldehyde.
 7. The method of claim1, where the dithiol is 1,6-hexanedithiol.
 8. The method of claim 1,where the polythioaminal is a linear polymer.
 9. A method of making ahydrophobic antifouling coating, the method comprising: forming a linearpolythioaminal polymer by reacting a fluorinated dianiline derivativewith a paraformaldehyde to form an intermediate imine, and then reactingthe intermediate imine with a dithiol; disposing the linearpolythioaminal polymer on a surface of a substrate; and increasing atemperature of the linear polythioaminal polymer to crosslink the linearpolythioaminal polymer and increase a contact angle of the substratewith crosslinked polythioaminal.
 10. The method of claim 9, where thesubstrate is a surface of a medical device.
 11. The method of claim 10,where the medical device is an implantable medical device.
 12. Themethod of claim 9, where the contact angle is at least 100°.
 13. Themethod of claim 9, where the temperature is increased to at least 100°C.
 14. The method of claim 9, where the dithiol is 1,6-hexanedithiol.15. A method of making a hydrophobic coating on a surface of a medicaldevice, the method comprising: forming a polythioaminal polymer byreacting a fluorinated aniline with an aldehyde to form an intermediateimine, and then reacting the intermediate imine with a dithiol;depositing the polythioaminal polymer on a surface of the medicaldevice; and increasing a temperature of the polythioaminal polymer toincrease a contact angle of the polythioaminal polymer with the surfaceof the medical device.
 16. The method of claim 15, wherein the aldehydeis paraformaldehyde.
 17. The method of claim 15, wherein forming thepolythioaminal polymer forms a linear polymer.
 18. The method of claim17, wherein increasing the temperature of the polythioaminal polymerinduces crosslinking by forming substitutions at nitrogen groups. 19.The method of claim 15, wherein a polydispersity index (PDI) of thepolythioaminal polymer is about
 2. 20. The method of claim 19, whereinincreasing the temperature increases the PDI of the polythioaminalpolymer.